Augmenting Effects of L-DOPS With Carbidopa and Entacapone: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Augmenting Effects of L-DOPS With Carbidopa and Entacapone (NCT00547911), a non-randomized phase 1, phase 2 study. The primary outcome is Plasma LDOPS Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone.

2. Clinical Question

3. Trial Design

The registry lists this as a Phase 1 and Phase 2 study with a crossover model, no masking, and an allocation classification of non-randomized. Enrollment is recorded as 14, and the study status is terminated. The recorded start is 2007-10 and primary completion is 2013-04.

The intervention descriptions say every participant received droxidopa with placebo, carbidopa, and entacapone on separate occasions. They also say the order of the three interventions was randomly assigned. This sequence randomization description sits alongside the registry's non-randomized allocation classification. The record does not explain that classification further. The six listed arm descriptions represent different possible sequences, rather than six independent parallel treatment groups. Because participants were intended to receive each condition, the main comparison is within participants.

The crossover structure can help control for stable differences between participants: each participant can serve as their own comparison across the conditions. But interpretation depends on the measurements being available and comparable across periods. The brief description refers to washout between testing phases, but the intervention descriptions are truncated, and a complete protocol is not reported in the registry record. The details of how sequence, period, and possible carryover effects were handled in analysis are not reported in the registry record.

The primary endpoint description says healthy volunteers and all patient groups were combined for analysis because of the low number of participants after premature termination. It also notes that some subject data could not be analyzed because measurements were unreliable. The number of participants who contributed usable endpoint data, and whether all participants completed every condition, are not reported in the registry record. No statistical analysis results are posted.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Data for Healthy Volunteers and all Patient groups was combined for analysis due to the low N-value because of premature study termination, which is further described in the "Limitations and Caveats" section. In addition, some subject data was unable to be analyzed due to unreliable measurements.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Plasma LDOPS Concentrations After 400 mg of Droxidopa + 200 mg of Either Placebo, Carbidopa, or Entacapone, measured over Up to 48 hours after receiving drug(s).

The primary endpoint was plasma L-DOPS concentration after administration of 400 mg of droxidopa with 200 mg of placebo, carbidopa, or entacapone. The registry describes concentrations in nmol/L and identifies the summary measure as a mean with standard error. Blood was sampled at baseline and at 1 hour, 2 hours, 3 hours, 6 hours, 24 hours, and 48 hours after drug administration. The stated timeframe is up to 48 hours.

Plasma concentration is a measure of the amount of the study drug present in the blood at sampled times. In general, repeated concentration measurements can describe how exposure changes over time and can support comparisons of exposure under different co-administered conditions. Such a measurement addresses a pharmacologic question; by itself, it is not a measure of symptoms or other clinical benefit.

The registry's stated rationale was to explore whether carbidopa or entacapone augments the effects of L-DOPS. The posted primary-outcome description identifies what was measured, but no concentration values, estimated contrasts, confidence intervals, or p-values are reported in the registry record. It is therefore not possible to assess the direction, size, or precision of any difference between the conditions from the posted primary endpoint information.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a crossover design compare?

In a crossover study, participants receive more than one study condition at different times. The primary comparison can therefore be made within the same participant, rather than by comparing one group assigned only to one condition with another group assigned only to a different condition. This can be useful when participants differ substantially from one another, because stable individual characteristics are shared across their measurements.

This design also creates analytic considerations. Measurements may depend on the treatment condition, the period in which it was given, the order of conditions, and whether an earlier condition has lingering effects. A washout period is intended to separate periods, but the registry's description does not provide enough detail to determine how washout, period effects, or carryover were assessed. The analysis method for these design features is not reported in the registry record.

What does the mean and standard error describe?

The primary outcome is described as a mean, with standard error as its dispersion measure. A mean expresses the central level of a continuous measurement, such as plasma concentration. The standard error describes the statistical uncertainty around an estimated mean; it is not a measure of the spread of individual participants' measurements. A confidence interval, if reported, would give a range of values compatible with the data under the chosen statistical method and assumptions. No confidence interval is reported for this endpoint.

Repeated concentration measurements are collected at baseline and several post-dose times. In general, observations from the same participant are related rather than independent. Statistical methods for repeated measurements account for that dependence when estimating changes over time or differences between conditions. The registry record does not report whether such a method was used, how baseline measurements entered the analysis, or whether separate time-specific comparisons were conducted.

Why does missing or unreliable measurement matter?

The primary-outcome description says some subject data could not be analyzed because measurements were unreliable. If measurements are unavailable, the number and pattern of missing observations can affect which participants and time points contribute to a summary. In general, missing-data methods rely on assumptions about why observations are missing. For example, conclusions can differ depending on whether missingness is unrelated to the outcome or connected to participant characteristics or measured values. The registry does not report the number of unreliable measurements, reasons by participant or condition, or any missing-data method.

What can be learned from the posted statistical information?

The registry lists seven outcome measures but zero analyses. No estimates or inferential statistics for the primary outcome are posted. Without an estimate, its uncertainty, and a description of the analysis, a reader cannot assess the magnitude or precision of a comparison. A p-value alone would not describe effect size, and an estimate without an uncertainty measure would not show how precisely it was measured. Neither is available in the registry record.

The record also does not report the planned sample-size justification, the statistical analysis plan, or whether any interim analyses occurred. These matters cannot be inferred from the phase labels, enrollment, or termination status. The planning illustrations associated with the page use a two-sided significance level of 0.05, equal allocation, and a normal approximation, with effects framed as fractions of an observed effect. They are planning illustrations rather than observed power. Because the posted endpoint results do not include an observed effect estimate, those illustrations should not be treated as evidence about the trial's actual findings.

More generally, a confidence interval gives information about both the direction and precision of an estimated effect, while a test addresses compatibility with a specified null hypothesis under its assumptions. Statistical significance is not a measure of clinical importance. These are general principles; the registry does not report an effect estimate, confidence interval, or test result for this study.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists seven outcome measures, including the primary plasma L-DOPS concentration endpoint and secondary measures of systolic blood pressure, diastolic blood pressure, and heart rate. It reports zero analyses. No outcome-specific estimates or tests are posted, and the registry record does not report how many comparisons were planned or performed.

When a study examines several outcomes, time points, or treatment contrasts, the chance of obtaining an apparently notable result by chance can increase if many tests are considered. In general, a statistical plan may prespecify a primary comparison or use methods to account for multiple testing. The registry record does not report a multiplicity strategy, a hierarchy of comparisons, or whether the listed time points were analyzed separately. It is therefore not possible to determine how multiplicity was handled.

Missingness is also relevant. The primary-outcome description says some subject data could not be analyzed because measurements were unreliable and that participant groups were combined because of low numbers after premature termination. It does not report how many measurements or participants were excluded, whether missingness varied across conditions or times, or what assumptions were used. The number analyzed for each endpoint is not reported in the registry record.

The stated combined analysis population limits interpretation of any potential differences among healthy volunteers and patient groups; no subgroup results are reported. The registry record also does not describe an intention-to-treat population, a per-protocol population, or another prespecified analysis population. With no posted analyses, the impact of missing data, outcome multiplicity, and analysis-population choices cannot be evaluated.

11. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent serious adverse event terms

Serious events with the highest arm-level rate: deep vein thrombosis followed by pulmonary embolism (50.0%).

The safety record is organized by intervention sequence, and each listed sequence group includes participants who received the three study conditions in a different order. It reports two participants at risk in each of four sequence groups and three at risk in each of two sequence groups. One serious adverse event is recorded in the group whose sequence was droxidopa with carbidopa, then droxidopa with entacapone, then droxidopa with placebo. The other listed sequence groups report no serious adverse events. Each group reports zero other adverse events.

The registry identifies “Deep Vein Thrombosis followed by Pulmonary Embolism” as the top serious-event term and gives 50.0%. The denominator or precise basis for that percentage is not reported in the registry record, so it should not be read as the percentage of all participants or as a treatment-specific risk. The sequence groups also do not isolate exposure to one condition, because participants received all three combinations.

Deaths are recorded as null rather than as a count. The registry record does not report a death count in the information available for this analysis; null should not be interpreted as a confirmed zero. These safety figures are descriptive and, given the small groups and crossover exposure, do not establish comparative risks among the conditions.

12. What the Result Does, and Does Not, Mean

This record documents a study designed to examine plasma droxidopa concentrations after droxidopa was given with placebo, carbidopa, or entacapone. The crossover design was intended for each participant to experience all three conditions, and the concentration sampling schedule extended through 48 hours. The record also identifies blood pressure and heart rate as secondary outcomes.

What it does not establish is whether either co-administered drug changed plasma droxidopa concentrations, by how much, or with what precision. The registry does not report outcome estimates, confidence intervals, or p-values, and it lists zero analyses. The absence of posted results should not be interpreted as a finding of no difference. Nor does the planned pharmacologic endpoint, by itself, establish a change in symptoms or other clinical outcomes.

The study was terminated, with 14 participants enrolled. The primary endpoint description says data from healthy volunteers and patient groups were combined because the number was low after premature termination, and that some data were unusable because of unreliable measurements. The number contributing usable data is not reported. These limitations make the evidence difficult to assess even apart from the absence of results.

The safety record includes one serious adverse event in one sequence group and identifies a serious-event term, but the available figures do not support a treatment-specific safety comparison. Each participant's exposure across conditions and the small sequence groups make attribution especially uncertain. Overall, the registry record supports a description of the research question, design, and some safety reporting, but not a conclusion about comparative effects or risks.

13. Why This Trial Matters Statistically

This trial is statistically notable because it combines a within-participant crossover structure with repeated measurements over time. In general, a crossover can make efficient use of participant data by comparing conditions within individuals. Repeated concentration measurements can also describe the time course of exposure. Both features require analysis that respects the dependence among observations rather than treating every measurement as independent.

The record illustrates why design labels and analysis details matter. It classifies allocation as non-randomized while intervention descriptions say the order of conditions was randomly assigned. Those statements describe different aspects of the design: sequence order may be randomized even when the registry's allocation field says non-randomized. The record does not explain the classification, so readers should not mistake the sequence categories for parallel treatment arms.

It also demonstrates the limits of enrollment as a guide to information. The registry reports 14 enrolled participants, but also notes premature termination, combined populations, and unreliable measurements that could not be analyzed. The usable data count for each condition and time point is not reported. Without that information and without effect estimates or uncertainty measures, the strength and precision of any comparison cannot be judged.

Finally, the record lists outcomes but no analyses. A transparent statistical interpretation depends on reported estimates, uncertainty, analysis populations, and methods for missing data and multiplicity. Their absence means the study's planned pharmacologic question is clear, while the evidence needed to answer it is not available in the posted results.

14. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The central limitation is that outcome results are not reported in the registry record. Although plasma concentrations are named as the primary endpoint and seven outcome measures are listed, the record reports zero analyses. No means, standard errors, contrasts, confidence intervals, or p-values are available for the primary or secondary outcomes.

The study was terminated after enrollment of 14 participants. The primary-outcome description says healthy volunteers and all patient groups were combined because of low numbers following premature termination. It also says some subject data were excluded from analysis because measurements were unreliable. The number of participants with usable measurements, completeness across the three conditions, and reasons for termination are not reported in the registry record.

The registry describes a crossover design and randomized intervention order, but classifies allocation as non-randomized. It does not explain this classification or report how sequence and period effects, carryover, or repeated observations were addressed. The full protocol, statistical analysis plan, sample-size justification, and interim-analysis information are not reported in the registry record.

The listed safety data are grouped by sequence, with small numbers at risk in each group. Participants received all three conditions, so those groups do not provide a straightforward comparison of exposure to one condition versus another. The basis for the serious-event percentage and a death count are not reported in the registry record. Together, these gaps prevent reliable assessment of comparative efficacy or safety from the posted information.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Augmenting Effects of L-DOPS With Carbidopa and Entacapone — NCT00547911.
• Registry record last updated 2014-07-17; status last verified 2014-06.
• Results first posted 2014-07-17.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

18. Record Summary

This Phase 1 and Phase 2 crossover study examined droxidopa (L-DOPS) with placebo, carbidopa, or entacapone. The registry reports 14 participants enrolled, no masking, non-randomized allocation, and terminated status. Intervention descriptions say each participant received all three conditions and that their order was randomly assigned.

The primary outcome was mean plasma L-DOPS concentration, measured at baseline and through 48 hours after dosing. The registry notes that healthy volunteers and patient groups were combined because of low numbers after premature termination, and that some measurements were unreliable. It lists seven outcome measures and zero analyses. The primary and secondary outcome results, analysis methods, and number of participants with usable endpoint data are not reported in the registry record.

The safety record lists one serious adverse event in one sequence group and gives a serious-event term with a reported percentage; its denominator is not stated. A death count is not reported.